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The immunomodulatory potential of radiotherapy provides a strong rationale for its combination with immunotherapies and other immunostimulatory agents. However, current combinations yield suboptimal clinical benefits. As the mechanisms behind radiotherapy-induced immunomodulation are gradually unraveled, various key factors have been identified as critical modulators of this process, opening new possibilities for adapting radiotherapy to immunotherapy. Here, we discuss seven factors: dose‒fractionation regimens of radiotherapy (RT), sequence and timing of RT and immunotherapy, radiation field, type of ionizing radiation, normal tissue effects, choice of the lesion to irradiate and identification of biomarkers. Preclinical and clinical studies on the combination of immunotherapy and radiotherapy are discussed, novel immunotherapeutic approaches are highlighted and improvements in study design are suggested.